EP0002624A1 - 2-Benzazepine compounds, processes for their preparation and pharmaceutical compositions containing them - Google Patents

2-Benzazepine compounds, processes for their preparation and pharmaceutical compositions containing them Download PDF

Info

Publication number
EP0002624A1
EP0002624A1 EP78300863A EP78300863A EP0002624A1 EP 0002624 A1 EP0002624 A1 EP 0002624A1 EP 78300863 A EP78300863 A EP 78300863A EP 78300863 A EP78300863 A EP 78300863A EP 0002624 A1 EP0002624 A1 EP 0002624A1
Authority
EP
European Patent Office
Prior art keywords
benzazepine
tetrahydro
mole
acetyl
give
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78300863A
Other languages
German (de)
French (fr)
Other versions
EP0002624B1 (en
Inventor
William Edward Bondinell
Robert Grubb Pendleton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Corp
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Corp, SmithKline Beecham Corp filed Critical SmithKline Corp
Publication of EP0002624A1 publication Critical patent/EP0002624A1/en
Application granted granted Critical
Publication of EP0002624B1 publication Critical patent/EP0002624B1/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride

Definitions

  • This invention relates to 2-benzazepine compounds which inhibit the enzyme phenylethanolamine N-methyl-transferase, processes for the preparation of such compounds, and pharmaceutical compositions containing them.
  • Epinephrine is a hormone, synthesized in the adrenal medulla, which is released into the bood stream in response to stress and produces physiological changes which serve to prepare the animal to cope with stress. For example, epinephrine produces anxiety, an increase in blood pressure, acceleration of heart rate, and increase in cardiac output. These changes are detrimental in individuals with certain disease conditions such as angina pectoris, myocardial infarction and anxiety neuroses.
  • Phenylethanolamine N-methyltransferase catalyzes the final step in the biosynthesis of epinephrine, that is the transfer of a methyl group from S-adenosylmethionine to norepinephrine to produce epinephrine.
  • the compounds of this invention inhibit phenylethanolamine N-methyl- transferase and thus reduce the formation of epinephrine. They are therefore of value in situations where there is overproduction of epinephrine or where epinephrine production is detrimental.
  • R 1 and R 2 which are the same or different, are hydrogen, chloro, bromo, fluoro, iodo, trifluoromethyl, amino, nitro, hydroxy, sulfamyl, methylthion, methylsulfinyl, methylsulfonyl, trichloromethylsulfinyl, trichloromethylsulfonyl, trifluoromethylthion, trifluoromethylsulfinyl, trifluoromethylsulfonyl, lower alkyl and lower alkoxy of from 1 to 3 carbon atoms each, provided that R 1 and R 2 are not both hydrogen; and R 3 and R 4 , which are the same or different, are hydrogen or lower alkyl of from 1 to 3 carbon atoms; and pharmaceutically acceptable acid addition salts thereof.
  • Preferred compounds of this invention are represented by formula I above when R 1 and R 2 are chloro, trifluoromethyl or sulfamyl, and R 3 and R 4 are both hydrogen.
  • An advantageous compound of this invention is 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine.
  • the compounds of this invention can be prepared by the following procedure: where R 1 , R 2 , R 3 and R 4 are as defined above.
  • a substituted aniline is reacted with chloral hydrate, hydroxylamine hydrohloride, sodium sulfate, and hydrochloric acid, and then with concentrated sulfuric acid, to yield a 4-, 5-, or 4, 5-substituted isatin.
  • the isatin is treated with m-chloroperbenzoic acid, and then with sodium methoxide,to yield the 5-, 6- or 5, 6-substituted methyl anthranilate which in turn is converted into the correspondingly substituted methyl 3-[(2-carbomethoxy)phenyl]propionate by treating the anthranilate with sodium nitrite, methyl acrylate and cuprous chloride followed by reduction,
  • the propionate is reduced to the corresponding diol with lithium aluminium hydride or diborane, and cyclization is carried out by treating the diol with N,N-dimethylaniline, thionyl chloride, and then with benzylamine to yield the 8-, 9- or 8,9-substituted 2-benzyl-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • This 2-benzazepine is then treated with cyanogen bromide and acid to give the desired 8, 9- or 8,9-substituted 2,3,4,5-tetrahydro-lH-2-benzazepine.
  • the 2-benzyl group can be removed by catalytic hydrogenation.
  • N-substituted compounds of formula I are formed by converting the N-unsubstituted 2-benzazepine into an amide by reaction with a lower alkanoyl halide, and then reducing the amide, for example with diborane, to the desired N-substituted 2-benzazepine.
  • the benzazepine is first oxidized to the imine as shown above, and then treated with an organometallic agent such as a lower alkyl magnesium halide or a lower alkyl lithium to give the desired. product.
  • organometallic agent such as a lower alkyl magnesium halide or a lower alkyl lithium
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula 1 can be formed with organic and inorganic acids by methods known to the art.
  • the base of Formula I can be reacted with an organic or inorganic acid in a water miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or in a water immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
  • a water miscible solvent such as acetone or ethanol
  • a water immiscible solvent such as ethyl ether or chloroform
  • salts of this invention are the maleate, fumarate, benzoate, ascorbate, pamoate, succinate, bismethylene- salicylate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, mandelate, cinnamate, citraconate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate, theophylline acetates, hydrochloride, hydrobromide, sulfate, cyclohexylsulfamate, phosphate and nitrate salts,
  • the activity cf the compounds of this invention is demonstrated by inhibition of phenylethanolamine N-methyltransferase in vitro by the assay procedure described by Pendleton and Snow, Molecular Pharmacology, 9:718-725 (1973) at various compound concentrations.
  • mice were administered orally with either drug or vehicle control on a twice-a-day basis for seven consecutive days. On the morning of the next day they were again dosed, and two hours later they were sacrificed by decapitation. The adrenal glands were then removed and analyzed fluorometrically for both epinephrine and norepinephrine content. A compound is considered active as a PNMT inhibitor if it significantly (at least p ⁇ 0.05) decreases the adrenal epinephrine/norepinephrine ratio.
  • the preferred compound of this invention 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine significantly lowered the adrenal epinephrine/norepinephrine ratio (p ⁇ 0.001) at a daily dose of 25 mg./kg.
  • compositions which comprise a pharmaceutical carrier and, as active ingredient, a 2-benzazepine compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the active ingredient will be present in the compositions in an effective amount to inhibit phenylethanolamine N-methyltransferase.
  • compositions of this invention contain the active ingredient of Formula 1 in an amount of from about 50 mg. to about 1000 mg., advantageously from about 100 mg to about 500 mg., per dosage unit.
  • the pharmaceutical carrier can,for example, be a solid or a liquid.
  • solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
  • the amount of solid carrier can be varied widely, but preferably it will be from about 25 mg to about 1 gm.
  • liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt. 200-400), and water.
  • the carrier or diluent can include a time delay material well known to the art, for example glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • compositions can take the form of tablets, capsules, powders, troches, lozenges, syrups, emulsions, sterile injectable liquids, or liquid suspensions or solutions.
  • the pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing, or dissolving the ingredients as appropriate to the desired form of composition.
  • Phenylethano amine N-methyltransferase can be inhibited by administering to en animal a 2-benzazepine compound of the invention in an amount sufficient to inhibit phcnylethanolamine N-methyltransferase.
  • the compounds of the invention are administered in conventional dosage unit forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.
  • compounds of the invention will be iministered in a daily dosage regimen of from about 100 mg. to about 2000 mg. most preferably from about 2CJ mg. to about 1000 mg.
  • equal doses will be administered, preferably two to three times per day.
  • administration is carried out as described above, inhibition of phenylethanolamine N-methyltransferase is produced.
  • the route of administration of the pharmaceutical compositions of this invention is internal, either parenterally or preferably orally, in an amount to produce the desired biological activity.
  • the malonate is suspended in trifluoroacetic acid (30 ml.), warmed on a steam bath for 15 minutes, and evaporated to give 2-[(carbomethoxy-3-nitro)benzyl7malonic acid which is heated to effect decarboxylation and refluxed in 10% hydrochloric acid to give 3-[(2-carboxy-3-nitro)phenyl]-propionic acid.
  • reaction mixture is allowed to warm to 25°C and it is washed with 10% aqueous sodium carbonate, dried over sodium sulfate, and evaporated to yield 2- acetyl-8-methylsulfinyl-2,3,4,5-tetrahydro-lH-2-benzazepine whit is hydrolyzed as described in Example 4 to yield 8-methylsulfinyl-2,3,4,5-tetra-hydro-lH-2-benzazepine.
  • the above ingredients are mixed and filled into a hard gelatin capsule.
  • One capsule is given three times a day.
  • sucrose, calcium sulfate and 2-benzazepine are thoroughly mixed and granulated with hot 10% gelatin solution.
  • the wetted mass is passed through a No.6 mesh screen directly onto drying trays.
  • the granules are dried at 120°C and passed through a No.20 mesh screen, mixed with starch, talc and stearic acid, and compressed into tablets.
  • Two tablets are administered three times a day.

Abstract

This invention concerns a process for preparing 2- benzazepine compounds which inhibit the enzyme phenylethanolamine N-methyltransferase and show activity in reducing anxiety. The compounds produced have substituents in the 8- and/or 9-positions, and optionally substituents in the 1- and 2-positions. The compounds are prepared by debenzylating an appropriately substituted N-benzyl 2-benzazepine with optional acylation and reduction, or with optional ozidation and alkylation of the debenzylated product to introduce 2- and 1-position substituents, respectively. Acid addition salts of the compounds are also prepared.

Description

  • This invention relates to 2-benzazepine compounds which inhibit the enzyme phenylethanolamine N-methyl-transferase, processes for the preparation of such compounds, and pharmaceutical compositions containing them.
  • Epinephrine is a hormone, synthesized in the adrenal medulla, which is released into the bood stream in response to stress and produces physiological changes which serve to prepare the animal to cope with stress. For example, epinephrine produces anxiety, an increase in blood pressure, acceleration of heart rate, and increase in cardiac output. These changes are detrimental in individuals with certain disease conditions such as angina pectoris, myocardial infarction and anxiety neuroses.
  • Phenylethanolamine N-methyltransferase catalyzes the final step in the biosynthesis of epinephrine, that is the transfer of a methyl group from S-adenosylmethionine to norepinephrine to produce epinephrine.
  • The compounds of this invention inhibit phenylethanolamine N-methyl- transferase and thus reduce the formation of epinephrine. They are therefore of value in situations where there is overproduction of epinephrine or where epinephrine production is detrimental.
  • The compounds of this invention are of formula:
    Figure imgb0001
    where R1 and R2, which are the same or different, are hydrogen, chloro, bromo, fluoro, iodo, trifluoromethyl, amino, nitro, hydroxy, sulfamyl, methylthion, methylsulfinyl, methylsulfonyl, trichloromethylsulfinyl, trichloromethylsulfonyl, trifluoromethylthion, trifluoromethylsulfinyl, trifluoromethylsulfonyl, lower alkyl and lower alkoxy of from 1 to 3 carbon atoms each, provided that R1 and R2 are not both hydrogen; and R3 and R4, which are the same or different, are hydrogen or lower alkyl of from 1 to 3 carbon atoms; and pharmaceutically acceptable acid addition salts thereof.
  • Preferred compounds of this invention are represented by formula I above when R1 and R2 are chloro, trifluoromethyl or sulfamyl, and R3 and R4 are both hydrogen.
  • An advantageous compound of this invention is 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine.
  • The compounds of this invention can be prepared by the following procedure:
    Figure imgb0002
    Figure imgb0003
    where
    R1, R2, R3 and R4 are as defined above.
  • According to the above procedure, a substituted aniline is reacted with chloral hydrate, hydroxylamine hydrohloride, sodium sulfate, and hydrochloric acid, and then with concentrated sulfuric acid, to yield a 4-, 5-, or 4, 5-substituted isatin. The isatin is treated with m-chloroperbenzoic acid, and then with sodium methoxide,to yield the 5-, 6- or 5, 6-substituted methyl anthranilate which in turn is converted into the correspondingly substituted methyl 3-[(2-carbomethoxy)phenyl]propionate by treating the anthranilate with sodium nitrite, methyl acrylate and cuprous chloride followed by reduction,
  • The propionate is reduced to the corresponding diol with lithium aluminium hydride or diborane, and cyclization is carried out by treating the diol with N,N-dimethylaniline, thionyl chloride, and then with benzylamine to yield the 8-, 9- or 8,9-substituted 2-benzyl-2,3,4,5-tetrahydro-lH-2-benzazepine. This 2-benzazepine is then treated with cyanogen bromide and acid to give the desired 8, 9- or 8,9-substituted 2,3,4,5-tetrahydro-lH-2-benzazepine. Alternatively, the 2-benzyl group can be removed by catalytic hydrogenation.
  • The N-substituted compounds of formula I are formed by converting the N-unsubstituted 2-benzazepine into an amide by reaction with a lower alkanoyl halide, and then reducing the amide, for example with diborane, to the desired N-substituted 2-benzazepine.
  • When a compound of Formula I is desired where R4 is other than hydrogen, the benzazepine is first oxidized to the imine as shown above, and then treated with an organometallic agent such as a lower alkyl magnesium halide or a lower alkyl lithium to give the desired. product.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula 1 can be formed with organic and inorganic acids by methods known to the art. The base of Formula I can be reacted with an organic or inorganic acid in a water miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or in a water immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Examples of salts of this invention are the maleate, fumarate, benzoate, ascorbate, pamoate, succinate, bismethylene- salicylate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, mandelate, cinnamate, citraconate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate, theophylline acetates, hydrochloride, hydrobromide, sulfate, cyclohexylsulfamate, phosphate and nitrate salts,
  • 7-Chloro-2,3,4,5-tetrahydro-IH-2-benzazepine is known in the art, J. Chem. Soc. Perkin I, 782-3 (1973)
  • The activity cf the compounds of this invention is demonstrated by inhibition of phenylethanolamine N-methyltransferase in vitro by the assay procedure described by Pendleton and Snow, Molecular Pharmacology, 9:718-725 (1973) at various compound concentrations.
  • The following are results comparing 2-benzaze, The compounds of the invention with the 7-chloro prior art compound.
    Figure imgb0004
  • The results of this test clearly demonstrate that both the 8-chloro and the preferred compound of this invention, 8,9-dichloro-2-benzazepine, are greater inhibitors of PNMT than the known 7-chloro compound.
  • In addition, the activity of the compounds of this invention is demonstrated in vivo by their administration to mice at 50 mg./kg. per day for seven consecutive days. Male mice were dosed orally with either drug or vehicle control on a twice-a-day basis for seven consecutive days. On the morning of the next day they were again dosed, and two hours later they were sacrificed by decapitation. The adrenal glands were then removed and analyzed fluorometrically for both epinephrine and norepinephrine content. A compound is considered active as a PNMT inhibitor if it significantly (at least p<0.05) decreases the adrenal epinephrine/norepinephrine ratio. (R.G. Pendleton et al., J. Pharmacol Exp. Ther. 190:551-562, 1974 and R.G. Pendleton et al., J. Pharmacol. Exp. Ther. 197:623-632, 1976). The preferred compound of this invention 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine significantly lowered the adrenal epinephrine/norepinephrine ratio (p<0.001) at a daily dose of 25 mg./kg.
  • The invention also provides pharmaceutical compositions which comprise a pharmaceutical carrier and, as active ingredient, a 2-benzazepine compound of Formula 1 or a pharmaceutically acceptable salt thereof. The active ingredient will be present in the compositions in an effective amount to inhibit phenylethanolamine N-methyltransferase.
  • Preferably, the compositions of this invention contain the active ingredient of Formula 1 in an amount of from about 50 mg. to about 1000 mg., advantageously from about 100 mg to about 500 mg., per dosage unit.
  • The pharmaceutical carrier can,for example, be a solid or a liquid. Examples of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. The amount of solid carrier can be varied widely, but preferably it will be from about 25 mg to about 1 gm. Examples of liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt. 200-400), and water. The carrier or diluent can include a time delay material well known to the art, for example glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • A wide variety of pharmaceutical forms can be employed, for example the compositions can take the form of tablets, capsules, powders, troches, lozenges, syrups, emulsions, sterile injectable liquids, or liquid suspensions or solutions. The pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing, or dissolving the ingredients as appropriate to the desired form of composition.
  • Phenylethano:amine N-methyltransferase can be inhibited by administering to en animal a 2-benzazepine compound of the invention in an amount sufficient to inhibit phcnylethanolamine N-methyltransferase.
  • Preferably, the compounds of the invention are administered in conventional dosage unit forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.
  • Preferably, compounds of the invention will be iministered in a daily dosage regimen of from about 100 mg. to about 2000 mg. most preferably from about 2CJ mg. to about 1000 mg.
  • Advantageously, equal doses will be administered, preferably two to three times per day. When the administration is carried out as described above, inhibition of phenylethanolamine N-methyltransferase is produced.
  • The route of administration of the pharmaceutical compositions of this invention is internal, either parenterally or preferably orally, in an amount to produce the desired biological activity.
  • The following Examples illustrate the invention.
    • EXAMPLE 1
  • 80 g. of 3,4-dichloroaniline (0.5 mole) in concentrated hydrochloric acid (43 ml.) and water (300 ml.) were mixed with 90 g. of chloral hydrate (0.54 mole) in water (1.21.), 571 g. of sodium sulfate in water (725 ml.), and 110 g. of hydroxylamine hydrochloride (1.5 mole) in water (500 ml.), heated to reflux, cooled, and filtered to give 3,4-dichloro- isonitrosoacetanilide: mp 162-164 C.
  • 360 g. of the isonitrosoacetanilide (1.55 mole) were gradually added to concentrated sulfuric acid (1.51.) stirred at 90°C. The mixture was stirred for 30 minutes, cooled, poured onto crushed ice, and filtered. The filter cake was dissolved in 2N sodium hydroxide, filtered, acidified with acetic acid, and filtered to give 4,5-dichloroisatin: mp 46-248°C.
  • 220 g. of 4,5-dichloroisatin (1 mole) were suspended in ethyl acetate (1.1.) and reacted with 172 g. of m-chloroperbenzoic acid (1 mole), stirred, filtered, and washed to yield dichloroisatoic anhydride: mp 268-271°C. d.
  • 150 g. of the anhydride (0.65 mole) were suspended in dry methanol (750 ml.) and reacted with sodium methoxide. The mixture was refluxed 30 minutes until the evolution of carbon dioxide stopped. The mixture was cooled, filtered, acidified with acetic acid, and evaporated to yield methyl 5,6-dichloroanthranilate. The crude anthranilate was converted into the hydrochloride: mp 180-1830C. (sealed tube).
  • 108 g. of methyl 5,6-dichloroanthranilate hydrochloride (0.425 mole) in acetone (200 ml.), concentrated hydrochloric acid (120 ml.) and 120 g of ice were stirred, cooled and treated dropwise with a solution of 31 g. of sodium nitrite (0.45 mole) in water (70 ml.). 40 g. of methyl acrylate (0.47 mole) and 8 g. of cuprous chloride (0.08 mole) were added and the mixture was stirred at 10°C. until nitrogen evolution ceased. The mixture was stirred at 250C. for one hour, extracted with benzene, and the benzene extracts were washed with saline, dried and evaporated to give methyl 2-chloro-3-[(2-carbomethoxy-3,4-dichloro)phenyl]propionate.
  • 117 g. of the 2-chloro-propionate (0.36 mole) were dissolved in acetic acid (500 ml.), stirred at 90 C., and treated with excess powdered zinc added in small portions until the reaction was complete. The mixture was cooled, filtered, and the filtrate was evaporated and partitioned between chloroform and water. The chloroform extracts were washed with 5% aqueous bicarbonate and evaporated to give methyl 3-[(2-carbomethoxy-3,4-dichloro)phenyl]propionate, b.p. 170-190 C. (3 mm.Hg.).
  • 37 g. of this propionate (0.127 mole) in tetrahydrofuran (150 ml.) were reduced with 8.8 g. of lithium aluminum hydride (0.23 mole) at 0°C for 6 hours and at 25°C for 40 hours, and then cooled to 0°C. Ethyl acetate was added followed by water and then hydrochloric acid, and the mixture was extracted with chloroform to give 3-[(3,4-dichloro-2-hydroxymethyl)-phenyl]propanol.
  • 27 g. of the propanol (0.115 mole) were dissolved in chloroform (360 ml.) and 58.5 g. of N,N-dimethylaniline (0.48 mole), stirred,and cooled to 0°C.. 62 g. of thionyl chloride (0.53 mole) were then added over one hour. The mixture was stirred at 3°C for one hour and then at reflux for four hours. The mixture was cooled, poured onto crushed ice, and extracted with benzene. Evaporation gave 3-[(2-chloromethyl-3,4-dichloro)-phenyl]propyl chloride.
  • 30 g. of the propyl chloride (0.11 mole) and 35.5 g. of benzylamine (0.33 mole) in benzene (150 ml.) were refluxed for two days, the solvent evaporated, and heated at 95°C for six hours. The mixture was diluted with water and extracted with toluene to give 2-benzyl-8,9-dichloro-2,3, 4,5-tetrahydro-lH-2-benzazepine which was purified as the hydrochloride: mp 198-199°C.
  • 3.06 g. of 2-benzyl-8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (0.01 mole) stirred in benzene were treated with cyanogen bromide, refluxed, and evaporated to give 2-cyano-8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine: mp 132.5-134°C.
  • 2.1 g. of 2-cyano-8,9-dichloro-2,3,4,5,-tetrahydro-1H-2-benzazepine (0.009 mole) were refluxed with acetic acid (50 ml.) and concentrated hydrochloric acid (5 ml.) for 24 hours, evaporated, and the residue recrystallized from methanol-ether to give 8,9-dichloro-2,3,4,5-tetra- hydro-lH-2-benzazepine: mp 266-268°C
    • EXAMPLE 2
  • Following the procedure of Example 1, the following substituted isatin compounds:
    • 4-trifluoromethylisatin
    • 4-bromoisatin
    • 4-chloroisatin
    • 4-chloro-5-methoxyisatin
    • 4-iodoisatin
    • 5-bromo-4-chloroisatin
    • 5-trifluoromethylisatin
    • 4-chloro-5-methylisatin
    • 5-chloro-4-methylisatin
    • 4,5-dimethylisatin
      are used as starting materials to give the following products, respectively:
    • 9-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 9-chloro-8-methoxy-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 9-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 9-trifluoromethyl-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 8-bromo-9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 8-trifluoromethyl-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 9-chloro-8-methyl-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 8-chloro-9-methyl-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 8,9-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine
    EXAMPLE 3
  • Following the procedure of Example 1, the following substituted aniline compound:
    • 3,4-bis-(trifluoromethyl)aniline

    is used as starting material to give the following product: 8,9-bis-(trifluoromethyl)-2,3,4,5-tetrahydro-lH-2-benzazepine. EXAMPLE 4
  • 206 g. of methyl 3-[(2-carbomethoxy)phenyl]propionate (0.93 mole) were dissolved in concentrated sulfuric acid (2.1), stirred at -10°C., and treated with 84 g. of sodium nitrate (1.0 mole). The mixture was stirred for 3 hours as it warmed to 25 C, and it was then poured onto crushed ice and extracted with ether. The ether was washed, dried,and evaporated to give crude methyl 3-[(2-carbomethoxy-4 mtro)phenyl] propionate.
  • 26.7 g. of the propionate (0.1 mole) dissolved in tetrahydrofuran (100 ml.) were stirred and treated with diborane (0.25 M) in tetrahydrofuran (250 ml.). The mixture was refluxed for 16 hours, cooled, treated with methanol and evaporated. The residue was heated for 15 minutes with 10% hydrochloric acid, cooled, extracted with ether, and the ether was evaporated to give 3-[(2-hydroxymethyl-4-nitro)phenyl]propanol.
  • 100 g. of the propanol (0.475 mole) dissolved in pyridine (1.1.) stirred at 0°C. were treated with 120 g. of methanesulfonyl chloride (1.05 mole). The mixture was stirred below 15°C for 4 hours, poured into water, acidified with hydrochloric acid, and extracted with ether to give the dimesylate ester of 3-[(2-hydroxymethyl-4-nitro)phenyl]propanol.
  • 70 g. of the dimesylate (0.19 mole) dissolved in dimethylformamide (600 ml.) were treated with 120 g. of benzylamine (1.12 mole), stirred for 16 hours, diluted with water, and extracted with ether to give crude 2-benzyl-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine which was purified by chromatography.
  • 24.4 g of the 2-benzazepine (0.086 mole) in acetic acid (200 ml.) containing 3 g. of 102 palladium-on-carbon were hydrogenated until the theoretical amount of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to give 8-amino-2,3,4,5-tetrahydro-1H-2- benzazepine purified as the fumarate, mp: 190-191°C.
  • 14.4 g. of the benzazepine (0.089 mole) in ethyl acetate (150 ml.) containing 14.4 g. of isopropenyl acetate (0.144 mole) were refluxed for 16 hours and evaporated to give 2-acetyl-8-amino-2,3,4,5-tetrahydro-lH-2- benzazepine.
  • 3.0 g. of the benzazepine (0.0147 mole) dissolved in concentrated hydrochloric acid (30 ml.) were stirred at 0°C and treated with a solution of 1.3 g. of sodium nitrite (0.019 mole) in water (5 ml.). The solution of the diazonium salt was added to a stirred suspension of 4.5g. of cuprous chloride (0.045 mole) in water (5 ml.) and concentrated hydrochloric acid (45 ml.) maintained at -10°C. The mixture was stirred at 250 for one hour, poured onto crushed ice and extracted with ethyl acetate to give 2-acetyl-8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • 2.5 g. of the benzazepine (0.0112 mole) were refluxed with 10% hydrochloric acid for 16 hours, cooled, and the solvent was evaporated to give 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride: mp: 305-308°C.
    • EXAMPLE 5
  • 2.0 g. of 2-benzyl-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine (0.007 mole), as prepared in Example 4, were dissolved in toluene (20 ml.), stirred at 5°C., and treated with 2.0 g. of cyanogen bromide (0.018 mole) and stirred for one hour. The mixture was diluted with hexane, filtered, and evaporated to yield 2-cyano-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • 1.4 g. of the cyano compound (0.0065 mole) were refluxed in acetic acid (10 ml.) and concentrated hydrochloric acid (15 ml.) for 24 hours, cooled, evaporated, and purified as the bitartrate salt to give 8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine bitartrate, mp: 213.5-214.5°C.
    • EXAMPLE 6
  • Following the procedure of Example 4, 2-acetyl-8-amino-2,3,4,5-tetrahydro-lH-2-benzazepine is diazotized with sodium nitrite and hydrochloric acid or sulfuric acid.
  • The solution of the diazonium salt was treated with sodium fluo- borate or with cuprous bromide to give, after hydrolysis, respectively:
    • 8-fluoro-2,3,4,5-tetrahydro-lH-2-benzazepine, and
    • 8-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine
    EXAMPLE 7
  • Following the procedure of Example 4, substituting equivalent amounts of sulfuric acid for hydrochloric acid in the diazotization step, and adding the solution of diazonium salt to aqueous potassium iodide, gave, after hydrolysis, 8-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride, mp: 320-324°C.
    • EXAMPLE 8
  • 16.2 g. of 8-amino-2,3,4,5-tetrahydro-lH-2-benzazepine, as prepared in Example 4, (0.1 mole) and 20 g. of acetic anhydride (0.2 mole) in acetic acid (200 ml.) are stirred at 25°C for 16 hours, poured onto crushed ice, neutralized with ammonium hydroxide, and extracted with chloroform. The chloroform is evaporated to give 2-acetyl-8-acetamido-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • 22 g. of 2-acetyl-8-acetamido-2,3,4,5-tetrahydro-lH-2-benzazepine (0.1 mole) dissolved in acetic acid are added to a mixture of 48 g. of 90% fuming nitric acid (0.76 mole) and acetic acid (6 ml.) stirred in an ice bath so that the internal temperature does not exceed 15°C.
  • The mixture is stirred at 150C for one hour, and poured into water to give 2-acetyl-8-acetamido-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine , which is purified by chromatography and crystallization.
  • 2-Acetyl-8-acetamido-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine is hydrolyzed following the procedure of Example 1 to give 8-amino-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 9
  • 2.1 g. of 8-amino-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine (0.01 mole) in ethyl acetate (25 ml.) containing 2.1 g. of isopropenyl acetate (0.021 mole) is refluxed until acetylation is complete, and the mixture is evaporated to give 2-acetyl-8-amino-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine.
  • Following the procedure of Example 4, 2-acetyl-8-amino-9-nitro-2,3, 4,5-tetrahydro-IH-2-benzazepine is diazotized and converted into 2- acetyl-8-chloro-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine which is hydrolyzed in 10% hydrochloric acid to give 8-chloro-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 10
  • 2.68 g. of 2-acetyl-8-chloro-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine (0.01 mole) are dissolved in boiling ethanol (40 ml.) and a solution of 6.3 g. of sodium hydrosulfite (0.03 mole) in water (40 ml.) is added dropwise. The mixture is refluxed, evaporated, and the residue is partitioned between dilute ammonium hydroxide and ether. Evaporation of the ether gives 2-acetyl-9-amino-8-chloro-2,3,4,5-tetrahydro-lH-2- benzazepine which is hydrolyzed to give 9-amino-8-chloro-2,3,4,5-tetra- hydro-lH-2-benzazepine.
    • EXAMPLE 11
  • Following the procedure of Example 4, and substituting an equivalent amount of sulfuric acid for hydrochloric acid, 2-acetyl-9-amino-8-chloro-2,3,4,5-tetrahydror-1H-2-benzazepine is diazotized and the resulting solution is warmed to 50°C until nitrogen evolution ceases. The mixture is cooled and extracted with ether to give 2-acetyl-8-chloro-9-hydroxy-2, 3,4,5-tetrahydro-lH-2-benzazepine which is hydrolyzed to give 8-chloro-9-hydroxy-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 12
  • 2.4 g. of 2-acctyl-8-chloro-9-hydroxy-2,3,4,5-tetrahydro-lH-2-benzazepine (0.01 mole) stirred in dimethylformamide (20 ml.) are treated with 0.24 g. of sodium hydride (0.01 mole), and then with 1.4 g. of methyl iodide (0.01 mole), stirred, poured into water, and extracted with ether. The ether is washed and evaporated to yield 2-acetyl-8-chloro-9-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine which is hydrolyzed to give 8-chloro- 9-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 13
  • Following the procedure of Examples 4,6, and 7, 2-acetyl-8-amino-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine is converted into the following compounds:
    • 2-acetyl-8-fluoro-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-8-bromo-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-8-iodo-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine which upon hydrolysis yield respectively:
      • 8-fluoro-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
      • 8-bromo-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-iodo-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    EXAMPLE 14
  • Following the procedure of Example 10, the following compounds:
    • 2-acetyl-8-fluoro-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-8-bromo-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-8-iodo-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • respectively are converted into:
    • 2-acetyl-9-amino-8-fluoro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-9-amino-8-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-9-amino-8-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine and upon hydrolysis yield respectively:
      • 9-amino-8-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine
      • 9-amino-8-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 9-amino-8-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine
    EXAMPLE 15
  • 18.1 g. of 2-methyl-6-nitrobenzoic acid (0.1 mole) in acetone (200 ml.) are treated with 26 g. of N,N-diisopropylethylamine (0.2 mole) and 12.6 g. of dimethylsulfate (0.11 mole). The mixture is refluxed, evaporated, partitioned between chloroform and dilute hydrochloric acid, and the chloroform phase is evaporated to give methyl 2-methyl-6-nitrobenzoate.
  • 19.5 g. of methyl 2-methyl-6-nitrobenzoate (0.1 mole) is dissolved in carbon tetrachloride (1.51.), 18.7 g. of N-bromosuccinimide (0.105 mole) are added, the mixture is refluxed, irradiated with a GE Sunlamp, and small amounts of dibenzoyl peroxide are added at frequent intervals until the reaction is complete. The mixture is filtered and evaporated to yield methyl 2-bromomethyl-6-nitrobenzoate.
  • 2.7 g. of methyl 2-bromomethyl-6-nitrobenzoate (0.01 mole) in dimethylformamide (15 ml.) are added to a stirred mixture of 0.6 g. of sodium hydride (0.025 mole) and 2.2 g. of di-t-butyl malonate (0.01 mole) in dimethylformamide (15 ml,). The mixture is stirred for 30 minutes, poured onto crushed ice, extracted with ether, and the ether is evaporated to give di-t-butyl 2-[(2-carbomethoxy-3-nitro)benzyl]malonate.
  • The malonate is suspended in trifluoroacetic acid (30 ml.), warmed on a steam bath for 15 minutes, and evaporated to give 2-[(carbomethoxy-3-nitro)benzyl7malonic acid which is heated to effect decarboxylation and refluxed in 10% hydrochloric acid to give 3-[(2-carboxy-3-nitro)phenyl]-propionic acid.
  • Following the procedure of Example 4, the propionic acid is converted into 2-benzyl-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine and the benzazepine is converted into 9-amino-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 16
  • 2-Benzyl-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine is converted into 9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine according to the procedure of Example 5.
    • EXAMPLE 17
  • Following the procedure of Example 8, 9-amino-2,3,4,5-tetrahydro-lH-2-benzazepine is acetylated to give 2- acetyl-9-acetamido-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • Following the procedure of Examples 8,9, and 10, 2-acetyl-9-acetamido-2,3,4,5-tetrahydro-1H-2-benzazepine is converted into the following compounds:
    • 2-acetyl-9-amino-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-9-chloro-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-8-amino-9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine and upon hydrolysis they yield respectively:
      • 9-fluoro-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 9-chloro-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-amino-9-chloror-2,3,4,5-tetrahydro-1H-2-benzazepine
    EXAMPLE 18
  • 2.11 g. of 9-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (as prepared in Example 2) (0.01 mole) is refluxed in 48% hydrobromic acid, cooled, and evaporated to give 9-chloro-8-hydroxy-2,3,4,5-tetra- hydro-lH-2-benzazepine hydrobromide.
    • EXAMPLE 19
  • Following the procedure of Example 13, 2-acetyl-9-amino-8-nitro-2, 3,4,5-tetrahydro-1H-2,benzazepine is converted into 2-acetyl-9-fluoro-8-nitro-2,3,4,5-tetrahydro-lH-2,benzazepine
    • 2-acetyl-9-bromo-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-9-iodo-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine and the acetyl compounds are hydrolyzed to yield respectively:
      • 9-fluoro-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 9-bromo-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 9-iodo-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    EXAMPLE 20
  • Following the procedure of Example 14, the following compounds: ,
    • 2-acetyl-9-fluoro-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-9-bromo-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-9-iodo-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine are converted into:
    • 2-acetyl-8-amino-9-fluoro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-8-amino-9-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-8-amino-9-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine which are hydrolyzed in 10% hydrochloric acid to yield respectively:
      • 8-amino-9-fluoro-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-amino-9-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine
      • 8-amino-9-iodo-2,3,4,5-tetrahydro-1H-2-benzazepine
    EXAMPLE 21
  • 10 g. of 2-acetyl-2,3,4,5-tetrahydro-1H-2-benzazepine (0.05 mole) are added to chlorosulfonic acid (100 ml.) at -40°C, stirred at 25°C for 48 hours, poured onto crushed ice, extracted with ethyl acetate, and evaporated to give 2-acetyl-8-chlorosulfonyl-2,3,4,5-tetrahydro-1H-2- benzazepine.
  • 2.0 g. of the chlorosulfonyl compound (0.007 mole) were dissolved in tetrahydrofuran (10 ml.) and added to tetrahydrofuran (20 ml.) saturated with ammonia. The mixture was stirred for one hour, filtered, and the filter cake was crystallized from water to give 2-acetyl-8-sulfamyl-2,3, 4,5-tetrahydro-1H-2-benzazepine: mp 223-224°C.
  • 1.5 of the sulfamyl compound (0.006 mole) were refluxed in 10% hydrochloric acid for 8 hours, evaporated, and the residue was crystallized from isopropanol-ethyl acetate to give 8-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride: mp: 244-245 C.
    • EXAMPLE 22
  • Following the procedure of Example 1, 7-chloroisatin is converted into 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine which is acetylated according to the procedure of Example 8, and chlorosulfonated and then treated with ammonia following the procedure of Example 21 to give 2- acetyl-6-chloro-9-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine.
  • 3 g. of the 6-chloro-9-sulfamyl compound (0.01 mole) in methanol (100 ml.) containing 250 mg. of 10% palladium-on-carbon and 1.3 g. of N,N-diisopropylethylamine (0.01 mole) are reduced with hydrogen until the theoretical amount is absorbed. The mixture is filtered, evaporated, and the residue is crystallized to give 2-acetyl-9-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine which is hydrolyzed according to the procedure of Example 21 to give 9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 23
  • 0.9 g. of 2-acetyl-8-amino-9-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine (0.0038 moles) in concentrated hydrochloric acid (3 ml.) is stirred, cooled to 0°C, and diazotized by addition of 0.3 g. of sodium nitrite (0.0044 moles) dissolved in water (2 ml.). The solution of the diazonium salt is added to a mixture of dioxane saturated with sulfur dioxide (3 ml.), 0.4 g. of potassium chloride, and 0.3 g. of cupric chloride dihydrate. The mixture is stirred at 25°C for one hour and then at 40-60°C for 30 minutes. The mixture is diluted with water, extracted with ethyl acetate, and the solvent is evaporated to give crude 2-acetyl-9-chloro-8-chlorosulfonyl-2,3,4,5-tetrahydro-lH-2-benzazepine. The chlorosulfonyl compound is treated with ammonia and hydrolyzed following the procedure of Example 21 to give 9-chloro-8-sulfamyl-2,3,4,5-tetrahydro-lH-2- benzazepine.
    • EXAMPLE 24
  • Following the procedure of Example 23, the following compounds:
    • 2-acetyl-8-amino-9-fluoro-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-8-amino-9-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-8-amino-9-iodo-2,3,4,5-tetrahydro-lH-2-benzazepine are converted into the following compounds:
      • 2-acetyl-9-fluoro-8-sulfamy1-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 2-acetyl-9-bromo-8-sulfamyl-2,34,5-tetrahydro-1H-2-benzazepine
      • 2-acetyl-9-iodo-8-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine which are hydrolyzed to yeild respectively:
      • 9-fluoro-8-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine
      • 9-bromo-8-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 9-iodo-8-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
    EXAMPLE 25
  • Following the procedure of Example 23, 2-acetyl-8-amino-9-nitro-2,3, 4,5-tetrahydro-lH-2-benzazepine is converted into 2-acetyl-8-chlorosulfonyl-9-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine which is treated with ammonia to yield 2-acetyl-9-nitro-8-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine which upon hydrolysis gives 9-nitro-8-sulfamyl-2,3,4,5-tetra- hydro-lH-2-benzazepine.
    • EXAMPLE 26
  • 2.7 g. of 9-nitro-8-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine (0.01 mole) is reduced following the procedure of Example 4 to give 9-amino-8-sulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 27
  • 3.3 g. of 2-acetyl-8-chlorosulfonyl-9-nitro-2,3,4,5-tetrahydro-lH-2- benzazepine (0.01 mole) in tetrahydrofuran are treated with 4 g. of dibenzylamine (0.02 mole) to give 2-acetyl-8-N,N-dibenzylsulfamyl-9-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine which is reduced with sodium hydrosulfite following the procedure of Example 10 to give 2-acetyl-9-amino-8-N,N,-dibenzylsulfamyl-2,3,4,5-tetrahydro-1H-2-benzazepine which is diazotized and solvolyzed following the procedure of Example 11 to give 2-acetyl-8-N,N-dibenzylsulfamyl-9-hydroxy-2,3,4,5-tetrahydro-lH-2-benzazepine.
  • 4.6 g. of the 8-N,N-dibenzylsulfamyl compound (0.01 mole) are refluxed in trifluoroacetic acid until dibenzylation is complete, and then hydrolyzed following the procedure of Example 4 to give 9-hydroxy-8-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine,
    • EXAMPLE 28
  • 4.6 g. of 2-acetyl-8-N,N-dibenzylsulfamyl-9-hydroxy-2,3,4,5-tetra- hydro-lH-2-benzazepine (0.01 mole) are methylated following the procedure of Example 12 to give the 9-methoxy compound which is hydrolyzed following the procedure of Example 27 to give 9-methoxy-8-sulfamyl-2,3,4,5-tetra- hydro-lH-2-benzazepine.
    • EXAMPLE 29
  • Following the procedure of Example 23, the following compounds:
    • 2-acetyl-9-amino-8-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-9-amino-8-bromo-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-9-amino-8-i6do-2,3,4,5-tetrahydro-lH-2-benzazepine
    • 2-acetyl-9-amino-8-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine
    • 2-acetyl-9-amino-8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine are converted into, respectively:
      • 8-chloro-9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-bromo-9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-iodo-9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-fluoro-9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
      • 8-nitro-9-sulfamyl-2,3,4,5-tetrahydro-lH-2-benzazepine
    EXAMPLE 30
  • 2.3 g. of 2-acetyl-8-chlorosulfonyl-2,3,4,5-tetrahydro-lH-2-benzazepine (0.008 mole) are dissolved in 75 ml. of warm glacial acetic acid and treated at 75°C with 11.25 g. of stannous chloride dihydrate (0.05 mole) in concentrated hydrochloric acid (10 ml.). The reaction mixture is allowed to cool to 25°C, stirred for 1.5 hours, and poured into 250 ml. of water containing concentrated hydrochloric acid. Crude 2-acetyl-8-mercapto-2,3,4,5-tetrahydro-1H-2-benzazepine is isolated by filtration and dried.
  • 1.06 g. of the 2-acetyl-8-mercapto-2,3,4,5-tetrahydro-lH-2,benzazepine (0.0048 mole) are suspended in methanol (20. ml.), stirred in a nitrogen atmosphere, and 0.3 g. of sodium methoxide (0.0055 mole) is added followed by iodomethane (5 ml'.). The mixture is stirred at 25°C for thirty minutes, evaporated, and partitioned between chloroform and water. The chloroform layer is washed, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel eluted with ethyl acetate to give pure 2-acetyl-8-methylthio-2,3,4,5-tetrahydro-1H-2- benzazepine which is hydrolyzed following the procedure of Example 4 to give 8-methylthio-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 31
  • 2.1 g. of 2-acetyl-8-methylthio-2,3,4,5-tetrahydro-1H-2-benzazepine (0.009 mole) dissolved in chloroform (20 ml.) are cooled to -200C and treated with 1.6 g of m-ctloroperbenzoic acid (0.009 mole). The reaction mixture is allowed to warm to 25°C and it is washed with 10% aqueous sodium carbonate, dried over sodium sulfate, and evaporated to yield 2- acetyl-8-methylsulfinyl-2,3,4,5-tetrahydro-lH-2-benzazepine whit is hydrolyzed as described in Example 4 to yield 8-methylsulfinyl-2,3,4,5-tetra-hydro-lH-2-benzazepine.
    • EXAMPLE 32
  • 2.1 g. of 2-acetyl-8-methylthio-2,3,4,5-tetrahydro-lH-2-benzazepine (0.009 mole) dissolved in chloroform (20 ml.) are treated with 3.1 g. of m-chloroperbenzoic acid (0.018 mole). The reaction mixture is stirred at 250C, washed with 5% aqueous sodium carbonate, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel eluted with ethanol-ethyl acetate to yield 2racetyl-8-methylsulfonyl-2,3,4,5-tetrahydro-lH-2-benzazepine which is hydrolyzed as described in Example 4 to give 8-methylsulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 33
  • 11.8 g. of 2-acetyl-8-methylthio-2,3,4,5-tetrahydro-lH-2-benzazepine (0.05 mole) are dissolved in ethanol-free chloroform (250ml.)' containing 10 g. of cumene and stirred in the dark. Chlorine is passed through the solution for two days. The solvent is evaporated, and the residue is chromatographed on silica gel eluted with ethyl acetate to give 2-acetyl-8-trichloromethylthio-2,3,4,5-tetrahydro-1H-2-benzazepine.
  • 5.8 g. of the 2-acetyl-8-trichloromethylthio-2,3,4,5-tetrahydro-lH-2-benzazepine (0.017 mole) are oxidized as described in Example 31, and the residue is chromatographed on silica gel eluted with ethyl acetate to yield 2-acetyl-8-trichloromethylsulfinyl-2,3,4,5-tetrahydro-1H-2-benzazepine which is hydrolyzed as described in Example 4 to give 8-trichloromethylsulfinyl-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 34
  • 5.8 g. of 2-acetyl-8-trichloromethylthio-2,3,4,5-tetrahydro-lH-2- benzazepine (0.017 mole) are oxidized as described in Example 32 to yield 2-acetyl-8-trichloromethylsulfonyl-2,3,4,5-tetrahydro-lH-2-benzazepine which is hydrolyzed as described in Example 4 to yield 8-trichloromethylsulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 35
  • 5.4 g. of 2-acetyl-8-trichloromethylthio-2,3,4,5-tetrahydro-lH-2- benzazepine (0.016 mole) are added to a mixture of 15 g. of antimony trifluoride and 1.5 g. of antimony pentachloride, and heated and stirred at 900C for one day.. The resulting tar is partitioned between chloroform and 3N hydrochloric acid, The chloroform extract is dried over sodium sulfate and evaporated to give 2-acetyl-8-trifluoromethylthio-2,3,4,5-tetrahydro-1H-2-benzazepine which is hydrolyzed as described in Example 4 to give 8-trifluoromethylthio-2,3,4,5-tetrahydro-lH-2-benzazepine.
    • EXAMPLE 36
  • 5.2 g. of 2-acetyl-8-trifluoromethylthio-2,3,4,5-tetrahydro-lH-2- benzazepine (0.018 mole) are oxidized and chromatographed as described in example 31 to yield 2-acetyl-8-trifluoromethylsulfinyl-2,3,4,5-tetrahylro-1H-2-benzazepine which is hydrolyzed as described in Example 4 to yield 8-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-2-benzazepine.
    • EXAMPLE 37
  • 5.2 g. of 2-acetyl-8-triuoromethylthio-2,3,4,5-tetrahydro-1H-2- benzazepine (0.018 mole) are oxidized as described in Example 32 and chromatographed on silica gel eluted with ethyl acetate to give 2-acetyl- 8-trifluoromethylsulfonyl -2,3,4,5-tetrahydro-1H-2-benzazepine which is hydrolyzed as described in Example 4 to give 8-trifluoromethylsulfonyl-2, 3,4,5-tetrahydro-1H-2-benzepine
    • EXAMPLE 38
  • 3.7 g. of 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine (0.017 mole) in 5% aqueous sodium carbonate (400 ml.) are treated with 9.5 g. of potassium nitrosodisulfonate (0.034 mole) and stirred for 16 hours. The mixture is extracted with chloroform and the chloroform evaporated to give 8,9-dichloro-4,5-dihycro-3H-2-benzazepine which is purified by chromatography.
  • 2.3 g. of 8,9-dichloro-4,5,-dihydro-3H-2-benzazepine (0.011 mole) in ether (20 ml.) are stirred and treated with methylmagnesium iodide (0.029 mole) in ether (10 ml.). The mixture is treated with water, filtered, and extracted with ethyl acetate to give 8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-2-benzazepine which is purified by chromatography and crystallization of an appropriate salt.
    • EXAMPLE 39
  • 2.2 g. of 8,8-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine (0.01 mole) are refluxed in ethyl formate (20 ml.) and the mixture is evaporated to give 8,9-dichloro-2-formyl-2,3,4,5-tetrahydro-lH-2-benzazepine which is dissolved in tetrahydrofuran (20 ml.), added to 1M diborane in tetrahydrofuran (20 ml.) at 0°C, refluxed for one hour, cooled, treated with methanol, and evaporated. The residue is heated on the steam bath with 10% hydrochloric acid, the mixture is evaporated, and the residue is crystallized to give 8,9-dichloro-2-methyl-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride.
    • EXAMPLE 40
  • Figure imgb0005
  • The above ingredients are mixed and filled into a hard gelatin capsule.
  • One capsule is given three times a day.
    • EXAMPLE 41
  • Figure imgb0006
    Figure imgb0007
  • The sucrose, calcium sulfate and 2-benzazepine are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a No.6 mesh screen directly onto drying trays. The granules are dried at 120°C and passed through a No.20 mesh screen, mixed with starch, talc and stearic acid, and compressed into tablets.
  • Two tablets are administered three times a day.

Claims (10)

1. A compound of the formula:
Figure imgb0008
where R1 and R2, which are the same or different, are hydrogen, chloro, bromo, fluoro, iodo, trifluoromethyl, amino, nitro, hydroxy, lower alkyl, lower alkoxy, sulfamyl, methylthio, methylsulfinyl, methylsulfonyl, trichloromethylsulfinyl, trichloromethylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, provided that both R1 and R2 are not both hydrogen; and R3 and R4, which are the same or different, are hydrogen or lower alkyl, each lower alkyl or lower alkoxy group containing from 1 to 3 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to Claim 1, characterized in that R3 and R4 are both hydrogen.
3. 8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzagepine.
4. A compound according to Claim 2, characterized in that R is sulfamyl and R2 is hydrogen.
5. A compound according to Claim 2, characterized in that R is sulfamyl and R2 is chloro.
6. A pharmaceutical composition characterized in that it comprises a pharmaceutical carrier and a compound as claimed in any of Claims 1 to. 5.
7. A process for preparing a compound according to Claim 1, characterized in that a compound of the formula:
Figure imgb0009
is debenzylated to yield an N-unsubstituted derivative, and
(a) to prepare compounds where R3 is lower alkyl, the product is N-alkylated by acylating the N-unsubstituted derivative followed by reduction of the resulting amide; or
(b) to prepare compounds where R4 is lower alkyl, the N-unsubstituted derivative is oxieized to the corresponding imine followed by treatment with an organometalli agent; and optionally forming a pharmaceutically acceptable acid addition salt thereof.
8. A process according to Claim 7, characterized in that R3 and R4 are both hydrogen.
9. A process according to Claim 8, characterized in that R1 and R2 are both chloro.
10. A process for preparing a compound according to Claim 1, the process being substantially as herein descr bed in any of the Examples.
EP78300863A 1977-12-21 1978-12-19 2-benzazepine compounds, processes for their preparation and pharmaceutical compositions containing them Expired EP0002624B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86289277A 1977-12-21 1977-12-21
US862892 1997-05-23

Publications (2)

Publication Number Publication Date
EP0002624A1 true EP0002624A1 (en) 1979-06-27
EP0002624B1 EP0002624B1 (en) 1981-10-14

Family

ID=25339656

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300863A Expired EP0002624B1 (en) 1977-12-21 1978-12-19 2-benzazepine compounds, processes for their preparation and pharmaceutical compositions containing them

Country Status (18)

Country Link
EP (1) EP0002624B1 (en)
JP (1) JPS5488285A (en)
AR (1) AR220361A1 (en)
AT (1) AT367410B (en)
AU (1) AU517619B2 (en)
CA (1) CA1090798A (en)
DE (1) DE2861177D1 (en)
DK (1) DK541078A (en)
ES (1) ES476108A1 (en)
FI (1) FI783838A (en)
HU (1) HU177901B (en)
IL (1) IL56237A0 (en)
IT (1) IT1100851B (en)
NO (1) NO146468C (en)
PH (1) PH14063A (en)
PT (1) PT68919A (en)
YU (1) YU303278A (en)
ZA (1) ZA786230B (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0032672A2 (en) * 1980-01-17 1981-07-29 BASF Aktiengesellschaft Process for the preparation of alkylesters of anthranilic acid
EP0041627A2 (en) * 1980-05-16 1981-12-16 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft 3H-2-benzazepines, intermediates, processes for preparing them and compositions containing them
EP0065229B1 (en) * 1981-05-19 1985-08-07 Dr. Karl Thomae GmbH Benzazepines, process for their preparation and their application as pharmaceutical preparations
WO2000023437A1 (en) * 1998-10-16 2000-04-27 Takeda Chemical Industries, Ltd. Nitrogenous fused heterocycle compounds, process for the preparation thereof and agents containing the same
WO2007004960A1 (en) * 2005-07-05 2007-01-11 Astrazeneca Ab New compounds, process for their preparation, intermediates, pharmaceutical compositions and their use in the treatment of 5-ht6 mediated disorders such as alzheimer’s desease, cognitive disorders, cognitive impairment associated with schizophrenia, obesity and parkinson’s disease
EP1904069A2 (en) * 2005-07-15 2008-04-02 AMR Technology, Inc. Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3828096A (en) * 1966-11-22 1974-08-06 Mc Neil Labor Inc 2-alkoxycarbonyl-3-aryl-propylamines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3828096A (en) * 1966-11-22 1974-08-06 Mc Neil Labor Inc 2-alkoxycarbonyl-3-aryl-propylamines

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0032672A2 (en) * 1980-01-17 1981-07-29 BASF Aktiengesellschaft Process for the preparation of alkylesters of anthranilic acid
EP0032672A3 (en) * 1980-01-17 1981-12-09 Basf Aktiengesellschaft Process for the preparation of alkylesters of anthranilic acid
EP0041627A2 (en) * 1980-05-16 1981-12-16 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft 3H-2-benzazepines, intermediates, processes for preparing them and compositions containing them
EP0041627A3 (en) * 1980-05-16 1982-02-24 F. Hoffmann-La Roche & Co. Aktiengesellschaft 3h-2-benzazepines, intermediates, processes for preparing them and compositions containing them
EP0065229B1 (en) * 1981-05-19 1985-08-07 Dr. Karl Thomae GmbH Benzazepines, process for their preparation and their application as pharmaceutical preparations
WO2000023437A1 (en) * 1998-10-16 2000-04-27 Takeda Chemical Industries, Ltd. Nitrogenous fused heterocycle compounds, process for the preparation thereof and agents containing the same
WO2007004960A1 (en) * 2005-07-05 2007-01-11 Astrazeneca Ab New compounds, process for their preparation, intermediates, pharmaceutical compositions and their use in the treatment of 5-ht6 mediated disorders such as alzheimer’s desease, cognitive disorders, cognitive impairment associated with schizophrenia, obesity and parkinson’s disease
EP1904069A2 (en) * 2005-07-15 2008-04-02 AMR Technology, Inc. Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
EP1904069A4 (en) * 2005-07-15 2010-08-18 Amr Technology Inc Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8791101B2 (en) 2005-07-15 2014-07-29 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Also Published As

Publication number Publication date
DK541078A (en) 1979-06-22
AU4265278A (en) 1979-06-28
JPS5488285A (en) 1979-07-13
AT367410B (en) 1982-07-12
ATA918878A (en) 1981-11-15
ZA786230B (en) 1979-10-31
HU177901B (en) 1982-01-28
AU517619B2 (en) 1981-08-13
CA1090798A (en) 1980-12-02
PT68919A (en) 1979-01-01
NO146468B (en) 1982-06-28
AR220361A1 (en) 1980-10-31
NO784235L (en) 1979-06-22
DE2861177D1 (en) 1981-12-24
PH14063A (en) 1981-01-26
EP0002624B1 (en) 1981-10-14
NO146468C (en) 1982-10-06
ES476108A1 (en) 1979-11-16
IT1100851B (en) 1985-09-28
FI783838A (en) 1979-06-22
IT7830974A0 (en) 1978-12-18
YU303278A (en) 1983-06-30
IL56237A0 (en) 1979-03-12

Similar Documents

Publication Publication Date Title
US4490371A (en) N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides
AU665207B2 (en) Quinazoline derivatives as acetylcholinesterase inhibitors
US3960911A (en) Ferrocene compounds and preparation
US4217349A (en) Benzisoxazole derivatives
NO129745B (en)
EP0002624B1 (en) 2-benzazepine compounds, processes for their preparation and pharmaceutical compositions containing them
US4427590A (en) Triazolobenzodiazepine derivatives
US4122176A (en) 3-(Piperazinoalkyl)-benz-2,1-isoxazoles
US3988339A (en) Pharmaceutical compositions and methods of inhibiting phenylethanolamine N-methyltransferase
EP0240859A2 (en) Lipoxygenase inhibiting compounds
US4128666A (en) 4 AND 5-Halo substituted 2-indanamine compounds
FI57105B (en) FREQUENCY REFRIGERATION FOR NEW S-TRIAZOLO (5,1-A) EQUIPMENT WITH BEARING CONDITIONS
US4554287A (en) Antihypertensive 7-[2-(dialkylamino)ethyl]-4-hydroxy-1,3-benzimidazol-2-ones
US4192888A (en) Pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase
US3745216A (en) Compositions and methods for producing hypotensive activity with imidazo and pyrimido(2,1-b)quinazoline compounds
DE2740836A1 (en) N-Acyl-fused ring indole derivs. - useful in human or veterinary medicine as antiphlogistics
US4228170A (en) 7- and/or 8-Sulfur substituted 1,2,3,4-tetrahydroisoquinoline compounds
CH650254A5 (en) QUINOLONES, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS CONTAINING THEM.
US3466281A (en) As-triazino(5,6-b)indoles
EP0138490B1 (en) 4-alkyl methylenedioxy-2-1[H]-quinazolinones
US3939164A (en) 7 AND 8-Halo substituted 1,2,3,4-tetrahydroisoquinoline compounds
US4242346A (en) Bis-2N-alkylene tetrahydroisoquinoline compounds
US4258049A (en) Inhibiting phenylethanolamine N-methyltransferase with thiadiazolo and oxadiazolotetrahydroisoquinolines
US4218464A (en) 4- and 5-Substituted 2,3-dihydro-1H-isoindoles, pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase
US4272531A (en) 3,3&#39;-Bis-methylene-1,3-benzo-thiazine compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB IT LU NL SE

17P Request for examination filed
ITF It: translation for a ep patent filed

Owner name: JACOBACCI & PERANI S.P.A.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): BE CH DE FR GB IT LU NL SE

REF Corresponds to:

Ref document number: 2861177

Country of ref document: DE

Date of ref document: 19811224

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19811231

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SMITHKLINE BECKMAN CORPORATION

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Free format text: SMITHKLINE BECKMAN CORPORATION

ITPR It: changes in ownership of a european patent

Owner name: CAMBIO RAGIONE SOCIALE;SMITH KLINE BECKMAN CORPORA

REG Reference to a national code

Ref country code: FR

Ref legal event code: CD

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19831006

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19831130

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19831231

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19841203

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19841213

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19841218

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19841220

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19850215

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19851231

Ref country code: BE

Effective date: 19851231

BERE Be: lapsed

Owner name: SMITHKLINE CORP.

Effective date: 19851231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19860701

GBPC Gb: european patent ceased through non-payment of renewal fee
NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19860829

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19860902

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

EUG Se: european patent has lapsed

Ref document number: 78300863.4

Effective date: 19851007

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT